Age, the APOE ?4 allele, and chromosomal sex appear to place women at increased risk for Alzheimer?s Dementia (AD) compared to age-matched men. The APOE gene is associated with an altered FEV1/FVC ratio in women and may influence the development of Alzheimer?s and other forms of dementia in the setting of interstitial lung disease. As part of the current R21, we published that decreased estrogen receptor (ER)? may promote disease promoting pathways in lung tissue and myofibroblasts isolated from patients with a fatal form of interstitial lung disease, idiopathic pulmonary fibrosis and the bleomycin (BLM) model of interstitial lung disease. Recent studies also highlight the role of ER regulation of APOE ?4 in brain tissue and cultured neurons. In preliminary data, we confirm that in the National (Nationwide) Inpatient Sample (NIS) database, older women with interstitial lung disease are at increased risk for the development of AD. Decreased ER? signaling may contribute to the increased risk of AD in elderly women leading to our hypothesis that modulating sex steroid hormone receptor activation by specifically stimulating ER? activation may slow the development of AD in the susceptible patient with interstitial lung disease. To test this hypothesis, we will utilize a mouse model that incorporates the ?4 variant of the gene APOE, which is closely associated with an increased risk of the sporadic form of AD and has an influence on lung disease. We will determine whether: A) BLM-induced lung disease accelerates amyloid deposition in APOE ?4 mice, a confirmed model of AD and B) the intervention of ER? agonist on the progression of BLM-induced lung disease influences the development of amyloid deposition in APOE ?4 mutant mice. This proposal has high impact since sex hormone receptor activation in the setting of lung disease could potentiate detrimental factors in females or protective factors in males on the subsequent development of AD. Discovery of these mechanisms may lead to new therapies that not only ameliorate age-associated lung disease, but also affect the course of dementia. We are uniquely positioned to carry out the proposed studies as we have a longstanding track record of research on the effects of gonadal hormones in aging and fibrotic diseases and AD.